Transdermal delivery device

ABSTRACT

A transdermal drug delivery device involving a backing bearing at least one adhesive layer of an acrylate copolymer and a therapeutically effective amount of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole. The device optionally further involves (i) a second adhesive layer of an acrylate copolymer and optionally a therapeutically effective amount of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, and (ii) a membrane intermediate the first and second adhesive layers.

This is a continuation of application Ser. No. 08/164,054 filed Dec. 8,1993, now U.S. Pat. No. 5,494,680.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to transdermal drug delivery devices. In anotheraspect this invention relates to pharmaceutical formulations containing(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole.

2. Description of the Related Art

Transdermal drug delivery devices are designed to deliver atherapeutically effective amount of drug across the skin of a patient.Devices known to the art include reservoir type devices involvingmembranes that control the rate of drug release to the skin and devicesinvolving a dispersion of the drug in a matrix such as a pressuresensitive adhesive. The skin however presents a substantial barrier toingress of foreign substances into the body. It is therefore oftendesirable or necessary to incorporate certain materials that enhance therate at which the drug passes through the skin. However the type ofdevice, the transdermal flux rate that is suitable, and the suitableformulation components are dependent upon the particular drug to bedelivered.

(S)-3-Methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is disclosed inInternational Publication Number WO 92/21339 and is described as aselective and potent agonist at neuronal nicotinic acetylcholinereceptors. It is said to be potentially useful in the treatment ofcognitive, neurological and mental disorders characterized by decreasedcholinergic function, such as, for example dementias, attentionalhyperactivity disorder and anxiety associated with cognitive impairmentand substance abuse withdrawal.

SUMMARY OF THE INVENTION

The present invention provides a transdermal delivery device comprising:

(A) a backing;

(B) an adhesive layer adhered to one surface of the backing andcomprising a homogeneous mixture of

(1) a copolymer comprising

(a) about 80 to 98 percent by weight of an alkyl acrylate ormethacrylate containing 4 to 10 carbon atoms in the alkyl group, basedon the weight of all monomers in the copolymer; and

(b) about 2 to 20 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and

(2) a therapeutically effective amount of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole.

The present invention also provides a transdermal delivery devicecomprising:

(A) a backing;

(B) an adhesive layer adhered to one surface of the backing andcomprising a homogeneous mixture of

(1) a copolymer comprising

(a) about 60 to 80 percent by weight of an alkyl acrylate ormethacrylate containing 4 to 10 carbon atoms in the alkyl group, basedon the weight of all monomers in the copolymer;

(b) about 4 to 9 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and

(c) about 15 to 35 percent by weight of vinyl acetate, based on theweight of all monomers in the copolymer; and

(2) a therapeutically effective amount of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole.

The present invention also provides a transdermal delivery devicecomprising:

(A) a backing;

(B) a first adhesive layer adhered to one surface of the backing andcomprising an adhesive selected from the group consisting of:

(1) a copolymer comprising

(a) about 80 to 98 percent by weight of an alkyl acrylate ormethacrylate containing 4 to 10 carbon atoms in the alkyl group, basedon the weight of all monomers in the copolymer; and

(b) about 2 to 20 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and

(2) a copolymer comprising

(a) about 60 to 80 percent by weight of an alkyl acrylate ormethacrylate containing 4 to 10 carbon atoms in the alkyl group, basedon the weight of all monomers in the copolymer;

(b) about 4 to 9 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and

(c) about 15 to 35 percent by weight of vinyl acetate, based on theweight of all monomers in the copolymer;

(C) a second adhesive layer comprising an adhesive selected from thegroup consisting of:

(1) a copolymer comprising

(a) about 80 to 98 percent by weight of an alkyl acrylate ormethacrylate containing 4 to 10 carbon atoms in the alkyl group, basedon the weight of all monomers in the copolymer; and

(b) about 2 to 20 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and

(2) a copolymer comprising

(a) about 60 to 80 percent by weight of an alkyl acrylate ormethacrylate containing 4 to 10 carbon atoms in the alkyl group, basedon the weight of all monomers in the copolymer;

(b) about 4 to 9 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and

(c) about 15 to 35 percent by weight of vinyl acetate, based on theweight of all monomers in the copolymer; and

(D) a membrane between the first and second adhesive layers, themembrane being permeable to(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole,

wherein at least one of said first and second adhesive layers furthercomprises a therapeutically effective amount of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole in admixturetherewith.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a section through an embodiment of the present inventioncontaining first and second adhesive layers with a membrane between thelayers.

FIG. 2 shows a perspective view of a diffusion cell used to determineskin penetration rates.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides transdermal drug delivery devicescontaining (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (sometimesreferred to herein as "the drug").

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is known and disclosedin International Publication Number WO 92/21339 (Garvey et al.),Examples 1 and 2 thereof being incorporated herein by reference. The(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is present in atransdermal delivery device of the invention in a therapeuticallyeffective amount. The amount that constitutes a therapeuticallyeffective amount varies according to the condition being treated, thesurface area of the skin over which the device is to be placed, andother components of the transdermal delivery device. Accordingly it isnot practical to enumerate particular preferred amounts but such can bereadily determined by those skilled in the art with due consideration ofthese factors. Generally, however,(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is present in at leastone adhesive layer of a device of the invention in an amount of about 5to 35 percent, preferably about 10 to 30 percent, by weight based on thetotal weight of the adhesive layer that contains the drug. In thoseembodiments of the invention involving both a first and a secondadhesive layer either or both of such adhesive layers can contain thedrug.

The drug exhibits substantial solubility in the copolymer component ofthe adhesive layer (described in detail below). Accordingly in apreferred embodiment of the invention the drug is substantially fullydissolved in the copolymer.

The adhesive layer or layers in a device of the invention are generallyabout 25-600 μm thick. The adhesives utilized in the practice of theinvention should be substantially chemically inert to(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole. Suitable acryliccopolymer pressure sensitive adhesives for use in one embodiment of theinvention comprise in an amount of about 80 to 98 percent by weight(based on the total weight of all the monomers in the copolymer),preferably 85 to 91 percent by weight of an alkyl acrylate ormethacrylate containing in the alkyl group 4 to 10 carbon atoms,preferably 6 to 10 carbon atoms, more preferably about 6 to 8 carbonatoms, and most preferably 8 carbon atoms. Examples of suitable alkylacrylates are n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl,isohexyl, 2-ethyloctyl, isooctyl and 2-ethylhexyl acrylates. The mostpreferred alkyl acrylate is isooctyl acrylate. These adhesives furthercomprise from about 2 to 20 percent by weight (based on the total weightof all the monomers in the copolymer) of a monomer selected from thegroup consisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone. The preferred monomersare acrylic acid, acrylamide and N-vinyl-2-pyrrolidone.

In another embodiment of the invention, the acrylic copolymer pressuresensitive adhesive comprises in an amount of about 60 to 80 percent byweight (based on the total weight of all the monomers in the copolymer),preferably 70 to 80 percent by weight of an alkyl acrylate ormethacrylate containing in the alkyl group 4 to 10 carbon atoms,preferably 6 to 10 carbon atoms, more preferably about 6 to 8 carbonatoms, and most preferably 8 carbon atoms. Examples of suitable alkylacrylates are n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl,isohexyl, 2-ethyloctyl, isooctyl and 2-ethylhexyl acrylates. The mostpreferred alkyl acrylate is isooctyl acrylate. These adhesives furthercomprise from about 4 to 9 percent by weight (based on the total weightof all the monomers in the copolymer) of a monomer selected from thegroup consisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone. The preferred monomer isacrylamide. These adhesives further comprise from about 15 to 35 percentby weight (based on the total weight of all the monomers in thecopolymer), and preferably 15 to 25 percent by weight of vinyl acetate.

Since pressure sensitive adhesives such as those described above areinherently tacky and are suitably heat and light stable, there is noneed to add tackifiers or stabilizers. However, such can be added ifdesired. The pressure sensitive adhesives can further comprise areinforcer (e.g., colloidal silicon dioxide) if desired.

It has been found that the addition of certain skin penetrationenhancers increases the penetration of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole in vitro compared to alike device not containing the skin penetration enhancer when thisphenomena is measured using the skin penetration model described below.Hence, the transdermal delivery devices of the invention can optionallyfurther comprise a skin penetration enhancer. Exemplary skin penetrationenhancers are disclosed, e.g., in J. Controlled Release, 1993, 25, 1(Santus et al.), and include fatty acids, fatty acid esters of lower(i.e., C₁ -C₄) alcohols, fatty acid monoglycerides, and fatty alcohols.Skin penetration enhancers that have been found to be suitable includelauryl alcohol, oleyl alcohol, and ethyl oleate.

A transdermal delivery device of the invention also comprises a backing.The backing is flexible such that the device conforms to the skin.Suitable backing materials include conventional flexible backingmaterials used for pressure sensitive tapes, such as polyethylene,particularly low density polyethylene, linear low density polyethylene,high density polyethylene, polyester polyethylene terephthalate,randomly oriented nylon fibers, polypropylene, ethylene-vinyl acetatecopolymer, polyurethane, rayon and the like. Backings that are layered,such as polyethylene-aluminum-polyethylene composites, are alsosuitable. The backing should be substantially inert to the ingredientsof the adhesive layer.

Some embodiments of the invention also comprise a membrane.Physiologically acceptable membranes that have adequate permeability to(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole are suitable for usein the devices of the invention. Examples of suitable materials for themanufacture of these membranes include polyethylene, low densitypolyethylene, linear low density polyethylene, high densitypolyethylene, polyurethane, nylon, and ethylene:vinyl acetatecopolymers. Membranes prepared from linear low density polyethylene andethylene:vinyl acetate copolymers are preferred. Examples of suitablephysical forms for the membrane include a continuous film (e.g.,polyethylene films), a macroporous membrane (e.g., polyethylene thermalformed netting), or a microporous membrane (e.g., a polyethylenemembrane such as COTRAN™ 9710 membrane, 3M). The membrane serves toimprove the structural integrity of a device of the invention. Furtherthe membrane can be rate controlling, i.e., the presence of the membranein the transdermal device changes the skin penetration profile of thedevice compared to a like device not having the membrane, as suchprofile is determined using the test method described below. Themembrane thickness will generally be from about 1 to 4 mil (25 to 100μm).

It is desirable for a transdermal device to have sufficiently littlecold flow such that it is stable upon storage. It is also required thatit adhere well to the skin. In order to achieve optimal adhesion andresistance to cold flow, at least the skin contacting adhesive layer(and preferably both adhesive layers if the device contains two adhesivelayers) preferably has a compliance value (measured according to thetest method set forth in detail below) of 2×10⁻⁵ to 4×10⁻⁵ cm² /dyne.Compliance values outside this range are also suitable, but thoseadhesive layers having substantially lower compliance values willgenerally have less than optimal adhesion to skin. Those havingsubstantially higher compliance values will generally have less thanoptimal cold flow and might leave residual adhesive when removed fromthe skin. Compliance is influenced by the chain length, degree ofcrosslinking (if any), and the constituent monomers in the adhesivecopolymers. Furthermore the drug and other excipients (e.g., skinpenetration enhancers) function to soften the adhesive copolymers andtherefore the amount of such components present in the adhesive layersalso affects compliance. Adhesive layers having optimal compliance canbe readily selected and prepared by those skilled in the art with dueconsideration of the factors affecting compliance.

The adhesive copolymers described above for use in a device of theinvention can be prepared by methods well known to those skilled in theart and described, for example, in U.S. Pat. RE 24,906 (Ulrich), thedisclosure of which is incorporated herein by reference. Thepolymerization reaction can be carried out using a free radicalinitiator such as an organic peroxide (e.g., benzoylperoxide) or anorganic azo compound (e.g., 2,2'-azobis(2,4-dimethylpentanenitrile)).

Transdermal delivery devices of the invention which comprise a backingand a single layer of adhesive are preferably prepared by combiningadhesive and (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole with anorganic solvent (e.g., ethyl acetate and methanol) to afford a coatingformulation. The total solids content of the coating formulation ispreferably in a range of about 15 to 40 percent by weight, and morepreferably in the range of about 20 to 35 percent by weight, based onthe total weight of the coating formulation. The mixture of adhesive,(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole and solvent is shakenat high speed until a homogeneous formulation is obtained, then allowedto stand to dissipate air bubbles. The resulting coating formulation isknife coated onto a suitable release liner to provide a predetermineduniform thickness of the coating formulation. Suitable release linersinclude conventional release liners comprising a known sheet materialsuch as a polyester web, a polyethylene web, or a polystyrene web, or apolyethylene-coated paper, coated with a suitable fluoropolymer orsilicone based coating. The coated release liner is then dried and thenlaminated onto a backing material using conventional methods.

An exemplary transdermal delivery device of the invention involving twoadhesive layers and an intermediate membrane is shown in FIG. 1. Device10 comprises a backing 12, first adhesive layer 14, second adhesivelayer 16 and membrane 18. Device 10 is prepared in two portions whichare then laminated together to form the final device. The upper (skindistal) portion of the device is prepared as described above for adevice comprising a single layer of adhesive by coating a formulationcontaining adhesive, (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazoleand solvent onto a release liner, drying the coated release liner thenlaminating to backing 12. The lower portion is prepared by coating aformulation containing adhesive, optionally(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole and solvent onto arelease liner, drying the coated release liner and then laminating tomembrane 16. The release liner is removed from the upper portion and itis laminated to the membrane surface of the lower portion to afford thefinal device. The coating formulation used to prepare the upper portioncan differ (e.g., it can contain a different adhesive or a differentconcentration of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole) fromthat used to prepare the lower portion. The thickness of the firstadhesive layer can differ from that of the second adhesive layer.

The transdermal delivery devices of the invention can be made in theform of an article such as a tape, a patch a sheet, a dressing or anyother form known to those skilled in the art. Generally the device willbe in the form of a patch of a size suitable to deliver a preselectedamount of (S)-3-methyl-5-(1-methyl-2pyrrolidinyl)isoxazole through theskin. Generally the device will have a surface area of about 1 cm² toabout 40 cm².

The examples set forth below are intended to illustrate the invention.

Preparation of Adhesive Copolymers

The adhesive copolymers used in the examples that follow were preparedgenerally according to the methods described below. The inherentviscosity values which are reported were measured by conventional meansusing a Cannon-Fenske #50 viscometer in a water bath controlled at 25°C. to measure the flow time of 10 milliliters of a polymer solution(0.15 g per deciliter of polymer in ethyl acetate).

Preparation of Isooctyl Acrylate: Acrylic Acid (94:6) Copolymer

Isooctyl acrylate (173.9 g), acrylic acid (11.1 g)azobisisobutyronitrile (0.37 g), ethyl acetate (313.425 g) andisopropanol (1.575 g) were placed in a 1 quart (946 mL) bottle. Themixture was deoxygenated by purging with nitrogen (1L/min) for 2minutes. The bottle was sealed and placed in a 55° C. rotating waterbath for 24 hours to effect essentially complete polymerization. Theinherent viscosity in ethyl acetate was 0.97 deciliter/gram.

Preparation of Isooctyl Acrylate: Acrylic Acid (90:10) Copolymer

Isooctyl acrylate (21.6 g), acrylic acid (2.4 g),2,2'-azobis(2,4-dimethylpentanenitrile) (0.05 g, VAZO™ 52, DuPont),ethyl acetate (34.2 g) and isopropanol (1.8 g) were placed in a 4 ounce(120 mL) bottle. The mixture was deoxygenated by purging with nitrogen(1L/min) for 2 minutes. The bottle was sealed and placed in a 45° C.rotating water bath for 24 hours. The bottle was opened and 0.05 g of2,2'-azobis(2,4-dimethylpentanenitrile) was added. The solution wasdeoxygenated as above, sealed and placed into the water bath for another24 hours at 45° C. The inherent viscosity in ethyl acetate was 0.651deciliter/gram.

Preparation of Isooctyl Acrylate:Acrylic Acid (85:15) Copolymer

This copolymer was prepared according to the method used to prepare the90:10 copolymer except that the initial charge contained 20.4 g ofisooctyl acrylate and 3.6 g of acrylic acid. The inherent viscosity inethyl acetate was 0.606 deciliter/gram.

Preparation of Isooctyl Acrylate: Acrylic Acid (80:20) Copolymer

This copolymer was prepared according to the method used to prepare the90:10 copolymer except that the initial charge contained 19.2 g ofisooctyl acrylate and 4.8 g of acrylic acid. The inherent viscosity inethyl acetate was 0.603 deciliter/gram.

Preparation of Isooctyl Acrylate: N-vinyl-2-pyrrolidone (91:9) Copolymer

Isooctyl acrylate (54.9 Kg), N-vinyl-2-pyrrolidone (5.4 Kg), and ethylacetate (93.6 Kg) were charged into a 75 gallon (285 liter) stainlesssteel reactor. The mixture was deoxygenated and heated to 55° C. After 5minutes at 55° C., azobisisobutyronitrile (30 g) premixed in ethylacetate (1 Kg) was charged to the reactor. Additional portions ofazobisisobutyronitrile (30 g) premixed with ethyl acetate (1 Kg) wereadded 4 hours after the start of the reaction and again at 8 hours. Thetemperature was maintained at 55° C. throughout the reaction. Thereaction was continued until complete. An antioxidant (61 g, IRGANOX™1010, Ciba-Geigy Corp.) and heptane (66.3 Kg) were added to the reactorand the contents mixed until homogeneous. The final copolymer had ameasured inherent viscosity of 1.67 deciliter/g in ethyl acetate.

Preparation of Isooctyl Acrylate: Acrylamide: Vinyl Acetate (75:5:20)Copolymer

A master batch was prepared by combining isooctyl acrylate (62 1.0 g),acrylamide (41.4 g), vinyl acetate (165.6 g), 2,2' azobis(2,4-dimethylpentanenitrile) (1,656 g, VAZO™ 52, DuPont), ethyl acetate(884.5 g) and methanol (87.48 g). A portion (400 g) of the resultingsolution was placed in a one quart (0.95 liter) amber glass bottle. Thebottle was purged for 2 minutes with nitrogen at a flow rate of 1 literper minute. The bottle was sealed and placed in a rotating water bath at45° C. for 24 hours to effect essentially complete polymerization. Thecopolymer was diluted with ethyl acetate: methanol (250 g, 90:10volume-to-volume) to 26.05% solids and had a measured inherent viscosityof 1.27 deciliter/g in ethyl acetate at a concentration of 0.15g/deciliter.

Preparation of Isooctyl Acrylate: Acrylamide: Vinyl Acetate (74:6:20)Copolymer

Isooctyl acrylate (148 g), acrylamide (12 g), vinyl acetate (40 g),2,2'azobis(2,4-dimethylpentanenitrile) (0.30 g), ethyl acetate (310 g)and methanol (30.7 g) were added to a glass bottle. The bottle waspurged with nitrogen for 3 minutes at a flow rate of 1 liter per minute.The bottle was sealed and placed in a rotating water bath at 45° C. for29.5 hours to effect essentially complete polymerization. The inherentviscosity in ethyl acetate was 1.20 deciliter/g.

Preparation of "Dry Adhesive"

Dry adhesive was prepared by knife coating a 25 to 30 percent solidssolution of the adhesive copolymer at a thickness of 20-25 mil (500-635μm) onto a release liner. The adhesive coated release liner was ovendried (3 minutes at 65° C., 3 minutes at 135° C., then 3 minutes at 177°C.) to remove solvent. The dried adhesive copolymer was then strippedoff the release liner and stored in a glass container.

Membranes

Some of the membranes used in the examples below are commerciallyavailable (e.g., COTRAN™ 9720 polyethylene film and COTRAN™ 9702controlled caliper membrane, both from 3M Company). Others were preparedfrom commercially available resins using conventional extrusion methods(e.g., thermal extrusion onto a quenching roll). Examples of suitableresins include ULTRATHENE™ ethylene-vinyl acetate (EVA) copolymers fromQuantum Chemical, ELVAX™ EVA copolymers from DuPont and DOWLEX linearlow density polyethylene resins from Dow Chemical Company. In theexamples that follow, the designation "X % EVA" means a membraneprepared from an ethylene-vinyl acetate copolymer which contains X %vinyl acetate incorporated.

Compliance Test Method

The compliance values given in the examples below were obtained using amodified version of the Creep Compliance Procedure described in U.S.Pat. No. 4,737,559 (Kellen), the disclosure of which is incorporatedherein by reference. The release liner is removed from a sample of thematerial to be tested. The exposed adhesive surface is folded back onitself in the lengthwise direction to produce a "sandwich"configuration, i.e., backing/adhesive/backing. The "sandwiched" sampleis passed through a laminator then two test samples of equal area arecut using a rectangular die. One test sample is centered on thestationary plate of a shear-creep rheometer with the long axis of thetest sample centered on the short axis of the plate. The small,non-stationary plate of the shear creep rheometer is centered over thefirst sample on the stationary plate such that the hook is facing up andtoward the front of the rheometer. The second test sample is centered onthe upper surface of the small, non-stationary plate matching the axialorientation of the first test sample. The large, non-stationary plate isplaced over the second test sample and the entire assembly is clampedinto place. The end of the small, non-stationary plate that is oppositethe end with the hook is connected to a chart recorder. A string isconnected to the hook of the small, non-stationary plate and extendedover the front pulley of the rheometer. A weight (500 g) is attached tothe free end of the string. The chart recorder is started and at thesame time the weight is quickly released so that it hangs free. Theweight is removed after exactly 3 minutes has elapsed. The displacementis read from the chart recorder. The compliance is then calculated usingthe equation: ##EQU1## where A is the area of one face of the testsample, h is the thickness of the adhesive mass, X is the displacementand f is the force due to the weight attached to the string. Where A isexpressed in cm², h in cm, X in cm and f in dynes, the compliance valueJ is given in cm² /dyne.

In Vitro Skin Penetration Test Method

The skin penetration data given in the examples below was obtained usingthe following test method. A Diffusion cell 20 of the type shown in FIG.2 is used. Two types of skin are used, hairless mouse skin or humancadaver skin (Dermatomed skin about 500 μm thick obtained from a skinbank). As shown in FIG. 2, the skin 22 is mounted epidermal side upbetween upper portion 24 and lower portion 26 of the cell, which areheld together by means of ball joint clamp 28.

The portion of the cell below the mounted skin is completely filled withreceptor fluid (0.1M phosphate buffer, pH 6) such that the receptorfluid is in contact with the skin. The receptor fluid is stirred using amagnetic stir bar and a magnetic stirrer (not illustrated). The samplingport 30 is covered except when in use.

When a transdermal delivery device is evaluated, the skin is placedacross the orifice of the lower portion of the diffusion cell, therelease liner is removed from a 2.0 cm² patch and the patch is appliedto the skin and pressed to cause uniform contact with the skin. Thediffusion cell is assembled and the lower portion is filled with 10 mLof warm (32° C.) receptor fluid.

The cell is then placed in a constant temperature (32°±2° C.) andhumidity (50±10% relative humidity) chamber. The receptor fluid isstirred by means of a magnetic stirrer throughout the experiment toassure a uniform sample and a reduced diffusion barrier on the dermalside of the skin. The entire volume of receptor fluid is withdrawn atspecified time intervals and immediately replaced with fresh fluid. Thewithdrawn fluid is filtered through a 0.45 μm filter. A 1 mL portion offiltrate is then analyzed for(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole using high performanceliquid chromatography (Column: 15 cm×4.6 mm ZORBAX™ RX-C18 (DuPont), 5μm particle size; Mobile Phase: acetonitrile/5 mM tetramethylammoniumhydroxide aqueous solution/triethylamine, 50%/50%/0.1% v/v/v; Flow Rate:1.5 mL/min; Detection: uv at 215 nm). The cumulative amount of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole penetrating the skinis calculated.

EXAMPLE 1

Dry adhesive (1.716 g of isooctyl acrylate:acrylic acid94:6),(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (0.3005 g) andsolvent (4.666 g of ethyl acetate:methanol 90:10 volume-to-volume) wereplaced in order in a glass vial. The vial was capped then agitated on aplatform shaker until a uniform formulation was obtained. Theformulation was knife coated at a thickness of 15 mil (381 μm) onto asilicone release liner. The resulting coated release liner was ovendried at 110° F. (43° C.) for 10 minutes. The resulting adhesive layercontained 85 percent by weight of the 94:6 isooctyl acrylate:acrylicacid copolymer and 15 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole. The dried adhesivecoated liner was laminated onto a polyethylene backing. The compliancewas measured according to the test method described above. A J-value of6.87×10⁻⁵ cm² /dynes was obtained. Patches (2.0 cm²) were die cut fromthe laminate and the skin penetration through hairless mouse skin wasdetermined using the test method described above. The skin penetrationdata is shown in Table 1 below. Each value is the average of twoindependent determinations.

EXAMPLE 2

Transdermal delivery devices were prepared according to the method ofExample 1 except that the adhesive used was an isooctylacrylate:N-vinylpyrrolidone 91:9 copolymer. The compliance was measuredand a J-value of 6.47×10⁻ cm² /dynes was obtained. Skin penetration(hairless mouse skin) data is shown in Table 1 below. Each value is theaverage of two independent determinations.

EXAMPLE 3

Transdermal delivery devices were prepared according to the method ofExample 1 except that the adhesive used was an isooctylacrylate:acrylamide:vinyl acetate 75:5:20 copolymer. The compliance wasmeasured and a J-value of 1.084×10⁻⁵ cm² /dynes was obtained. The skinpenetration (hairless mouse skin) data is shown in Table 1 below.

                  TABLE 1                                                         ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 4 hr      8 hr    12 hr   24 hr 48 hr                                  ______________________________________                                        1      193       348     464     628   754                                    2      446       657     739     775   779                                    3      269       452     566     655   673                                    ______________________________________                                    

EXAMPLE 4-9

Using the general method of Example 1 a set of transdermal deliverydevices in which the weight percent of drug((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole) was varied wasprepared. In each case the adhesive was an isooctylacrylate:acrylamide:vinyl acetate 75:5:20 copolymer. The weight percentof drug and J-values are shown in Table 2 below. The skin penetration(human cadaver skin) data is shown in Table 3 below. Each value is theaverage of three independent determinations.

                  TABLE 2                                                         ______________________________________                                        Example     Weight Percent                                                                            J-value                                               Number      Drug        (cm.sup.2 /dynes)                                     ______________________________________                                        4           5           0.362 × 10.sup.-5                               5           10          0.637 × 10.sup.-5                               6           5           0.770 × 10.sup.-5                               7           20          1.174 × 10.sup.-5                               8           25          1.462 × 10.sup.-5                               9           30          2.992 × 10.sup.-5                               ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr   4 hr      8 hr 12 hr   24 hr                                                                              48 hr                               ______________________________________                                        4      33     51        65   71      75   75                                  5      125    195       246  263     273  274                                 6      198    317       411  446     471  475                                 7      249    400       521  565     596  601                                 8      364    592       753  800     825  828                                 9      503    921       1220 1327    1393 1401                                ______________________________________                                    

EXAMPLES 10-13

Using the general method of Example 1, a set of transdermal deliverydevices in which the weight percent of acrylic acid in the adhesivecopolymer was varied was prepared. In each case the adhesive coating wasprepared using ethyl acetate as the solvent and the resulting adhesivelayer contained 15 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole. The adhesivecopolymer used and J-values are shown in Table 4 below. The skinpenetration (human cadaver skin) data is shown in Table 5 below. Eachvalue is the average of three independent determinations.

                  TABLE 4                                                         ______________________________________                                        Example     isooctyl acrylate:                                                                         J-value                                              Number      acrylic acid (cm.sup.2 /dynes)                                    ______________________________________                                        10          94:6          6.369 × 10.sup.-5                             11          90:10         4.115 × 10.sup.-5                             12          85:15        0.7892 × 10.sup.-5                             13          80:20        0.2152 × 10.sup.-5                             ______________________________________                                    

                  TABLE 5                                                         ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr   4 hr      8 hr 12 hr   24 hr                                                                              48 hr                               ______________________________________                                        10     139    269       427  520     646  730                                 11     115    230       381  475     613  722                                 12     34     71        132  181     277  378                                 13     18     38        72   103     170  254                                 ______________________________________                                    

EXAMPLES 14-16

Using the general method of Example 1 a set of transdermal deliverydevices in which the weight percent of drug((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole) was varied wasprepared. In each case the adhesive was an isooctyl acrylate:acrylicacid 85:15 copolymer. The weight percent of drug and J-values are shownin Table 6 below. The skin penetration (human cadaver skin) data isshown in Table 7 below. Each value is the average of three independentdeterminations.

                  TABLE 6                                                         ______________________________________                                        Example     Weight Percent                                                                            J-value                                               Number      Drug        (cm.sup.2 /dynes)                                     ______________________________________                                        14          15          0.80 × 10.sup.-5                                15          25          4.37 × 10.sup.-5                                16          35          37.4 × 10.sup.-5                                ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr   4 hr      8 hr 12 hr   24 hr                                                                              48 hr                               ______________________________________                                        14     20     48        89   121     192  298                                 15     46     110       197  260     389  523                                 16     346    677       1016 1207    1474 1666                                ______________________________________                                    

EXAMPLES 17-19

Using the general method of Example 1 a set of transdermal deliverydevices in which the weight percent of drug((S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole) was varied wasprepared. In each case the adhesive was an isooctyl acrylate:acrylicacid 80:20copolymer. The weight percent of drug and J-values are shownin Table 8 below. The skin penetration (human cadaver skin) data isshown in Table 9 below. Each value is the average of three independentdeterminations.

                  TABLE 8                                                         ______________________________________                                        Example     Weight Percent                                                                            J-Value                                               Number      Drug        (cm.sup.2 /dynes)                                     ______________________________________                                        17          25          0.406 × 10.sup.-5                               18          35          1.136 × 10.sup.-5                               19          45          21.73 × 10.sup.-5                               ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr   4 hr      8 hr 12 hr   24 hr                                                                              48 hr                               ______________________________________                                        17     42     86        143  188     304  470                                 18     109    201       310  381     524  694                                 19     449    756       1063 1230    1472 1664                                ______________________________________                                    

EXAMPLES 20-22

Using the general method of Example 1 a set of transdermal deliverydevices in which the adhesive layer incorporated an adhesive reinforcerwas prepared. In each example the adhesive used was an isooctylacrylate:acrylamide:vinyl acetate 75:5:20 copolymer and weight percentof (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole was present.Colloidal silicon dioxide (AEROSIL™ 200 available from Degussa Corp,Teeterboro, N.J.) was used as the reinforcer and was added to the glassvial prior to shaking. The weight percent of silica used and theJ-values are shown in Table 10 below. The skin penetration (humancadaver skin) data is shown in Table 11 below. Each value is the averageof three independent determinations.

                  TABLE 10                                                        ______________________________________                                        Example     Weight Percent                                                                            J-Value                                               Number      Silica      (cm.sup.2 /dynes)                                     ______________________________________                                        20          1           2.025 × 10.sup.-5                               21          2           1.584 × 10.sup.-5                               22          3           1.110 × 10.sup.-5                               ______________________________________                                    

                  TABLE 11                                                        ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr   4 hr      8 hr 12 hr   24 hr                                                                              48 hr                               ______________________________________                                        20     591    921       1157 1243    1307 1319                                21     560    926       1191 1281    1351 1370                                22     506    820       1044 1124    1194 1216                                ______________________________________                                    

EXAMPLES 23-28

Transdermal delivery devices having two distinct adhesive layersseparated by a membrane were prepared as follows.

The first adhesive layer was prepared as follows. Dry adhesive (7.0034 gof isooctyl acrylate:acrylamide:vinyl acetate 75:5:20),(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (3.0147 g) and solvent(32,045 g of ethyl acetate:methanol 90:10) were placed in order in aglass vial. The vial was capped then agitated on a platform shaker untila uniform formulation was obtained. The formulation was knife coated ata thickness of 18 mil (457 μm) onto a release liner (SCOTCHPAK™ 1022fluoropolymer coated release liner from 3M Company). The resultingcoated release liner was oven dried at 110° F. (43° C.) for 10 minutes.The resulting adhesive layer contained 70 percent by weight of the75:5:20 isooctyl acrylate:acrylamide:vinyl acetate copolymer and 30percent by weight of (S)-3-methyl-5-(1-methyl-2pyrrolidinyl)isoxazole.The dried adhesive coated liner was allowed to cool for about 5 minutesthen it was laminated onto a low density polyethylene backing (COTRAN™9720 polyethylene film available from 3M).

The second adhesive layer was prepared as follows. Dry adhesive (4.8051g of isooctyl acrylate:acrylamide:vinyl acetate 75:5:20),(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (1.1983 g) and solvent(18,013 g of ethyl acetate:methanol 90:10) were placed in order in aglass vial. The vial was agitated on a platform shaker until a uniformformulation was obtained. The formulation was knife coated at athickness of 16 mil (406 μm) onto SCOTCHPAK™ 1022 fluoropolymer coatedrelease liner. The resulting coated release liner was oven dried at 110°F. (43° C.) for 10 minutes. The resulting adhesive layer contained 80percent by weight of the 75:5:20 isooctylacrylate:acrylamide:vinylacetate copolymer and 20 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole. The dried adhesivecoated liner was laminated onto one of the membranes shown in Table 12below.

The release liner was removed from the first adhesive layer then thelayer was laminated to the membrane on the second adhesive layer.Patches (2.0 cm²) were die cut from the resulting laminate. Each patchconsisted of five layers: a backing, a first adhesive layer containing30 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, a membrane, a secondadhesive layer containing 20 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, and a release liner.The skin penetration (human cadaver skin) data is shown in Table 13below. Except as noted, each value is the average of three independentdeterminations.

                  TABLE 12                                                        ______________________________________                                        Example                                                                       Number        Membrane                                                        ______________________________________                                        23              2% EVA film.sup.1 (3 mil/76 μm)                            24            4.5% EVA film.sup.2 (2 mil/51 μm)                            25              9% EVA film.sup.3 (2 mil/51 μm)                            26             19% EVA film.sup.4 (2 mil/51 μm)                            27            polyurethane.sup.5 (2 mil/51 μm)                             28            microporous polyethylene.sup.6                                  ______________________________________                                         .sup.1 Prepared from NATR 187 Resin, Quantum Chemical                         .sup.2 Prepared from NATR 198 Resin, Quantum Chemical                         .sup.3 COTRAN ™ 9703, 3M                                                   .sup.4 Prepared from ULTRATHENE ™ UE631000, Quantum Chemical               .sup.5 Prepared from Dow Medical Grade 236380AE Resin                         .sup.6 COTRAN ™ 9710, 3M                                              

                  TABLE 13                                                        ______________________________________                                        Example Cumulative Amount Penetrating (μm/cm.sup.2)                        Number  2 hr   4 hr     8 hr 12 hr  24 hr 48 hr                               ______________________________________                                        23      .sup. 352.sup.1                                                                      .sup. 604.sup.1                                                                        .sup. 840.sup.1                                                                    .sup.  974.sup.1                                                                     .sup. 1177.sup.1                                                                    .sup. 1289.sup.1                    24      119    244      416   544    805   987                                25      .sup. 318.sup.1                                                                      .sup. 607.sup.1                                                                        .sup. 913.sup.1                                                                    .sup. 1092.sup.1                                                                     .sup. 1316.sup.1                                                                    .sup. 1428.sup.1                    26      .sup.  86.sup.1                                                                      .sup. 240.sup.1                                                                        .sup. 474.sup.1                                                                    .sup.  639.sup.1                                                                     .sup. .sup. 1229.sup.1                    27      .sup. 258.sup.1                                                                      .sup. 481.sup.1                                                                        .sup. 750.sup.1                                                                    .sup.  921.sup.1                                                                     .sup. 1166.sup.1                                                                    .sup. 1318.sup.1                    28      307    576      869  1038   1262  1394                                ______________________________________                                         .sup.1 Average of 2 independent determinations                           

EXAMPLES 29-37

Using the general method of Example 23, a set of multilayer transdermaldelivery devices was prepared. The compositions are shown in Table 14below. In each example the drug is(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole and the percent is byweight based on the total weight of the adhesive layer. All of themembranes used were 3 mil (76 μm) thick. The skin penetration (humancadaver skin) data is shown in Table 15 below. Each value is the averageof three independent determinations.

                  TABLE 14                                                        ______________________________________                                        Example                                                                              First                   Second                                         Number Adhesive Layer                                                                              Membrane  Adhesive Layer                                 ______________________________________                                        29     30% drug      9% EVA.sup.3                                                                            No drug                                               70% IOA:AA.sup.1        IOA:ACM:VA.sup.2                               30     30% drug      9% EVA.sup.3                                                                            No drug                                               70% IOA:AA              IOA:ACM:VA                                     31     30% drug      9% EVA.sup.3                                                                            20% drug                                              70% IOA:AA              80% IOA:ACM:VA                                 32     30% drug      None      No drug                                               70% IOA:AA              IOA:ACM:VA                                     33     30% drug      None      20% drug                                              70% IOA:AA              80% IOA:ACM:VA                                 34     30% drug      low density                                                                             20% drug                                              70% IOA:ACM:VA                                                                              poly-     80% IOA:ACM:VA                                                      ethylene.sup.4                                           35     30% drug      9% EVA.sup.3                                                                            20% drug                                              70% IOA:ACM:VA          80% IOA:ACM:VA                                 36     30% drug      low density                                                                             No drug                                               70% IOA:ACM:VA                                                                              poly-     IOA:ACM:VA                                                          ethylene.sup.4                                           37     30% drug      9% EVA.sup.3                                                                            No drug                                               70% IOA:ACM:VA          IOA:ACM:VA                                     ______________________________________                                         .sup.1 IOA:AA is isooctyl acrylate:acrylic acid 80:20 copolymer               .sup.2 IOA:ACM:VA is isooctyl acrylate:acrylamide:vinyl acetate 75:5:20       copolymer                                                                     .sup.3 COTRAN ™ 9703, 3M                                                   .sup.4 COTRAN ™ 9720, 3M                                              

                  TABLE 15                                                        ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr      4 hr    8 hr    12 hr 24 hr                                  ______________________________________                                        29.sup.1                                                                             133       278     532     720   1090                                   30.sup.2                                                                             40        130     336     516   904                                    31     419       801     1316    1664  2281                                   32     202       425     743     953   1325                                   33     374       829     1455    1843  2432                                   34     400       812     1332    1647  2269                                   35     591       1191    1970    2480  3314                                   36     137       270     495     682   1133                                   37     328       649     1099    1409  1944                                   ______________________________________                                         .sup.1 These patches were allowed to equilibrate for 4 hours prior to the     commencement of the skin penetration test                                     .sup.2 These patches were tested immediately after the final lamination       and die cutting.                                                         

EXAMPLE 38

The upper (skin distal) portion of the transdermal delivery device wasprepared as follows. Dry adhesive (332.05 g of isooctylacrylate:acrylamide:vinyl acetate 75:20),(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (115.46 g) and solvent(831.07 g of ethyl acetate:methanol 90:10) were placed in order in aglass jar. The jar was agitated on a platform shaker for about 24 hours.The formulation was allowed to stand until all air bubbles haddissipated. The formulation was knife coated at a thickness of 32 mils(813 μm)onto a SCOTCHPAK™ 1022 fluoropolymer coated release liner. Thecoated release liner was allowed to air dry at ambient temperature for20 minutes then it was immediately laminated to the polyester side ofSCOTCHPAK™ 1109 polyester film laminate (available from 3M).

The lower portion of the transdermal delivery device was prepared asfollows. A coating formulation containing isooctylacrylate:acrylamide:vinyl acetate 75:5:20 copolymer in ethylacetate:methanol 90:10 (35 percent solids) was knife coated at athickness of 7 mils (178 μm) onto a SCOTCHPAK™ 1022 fluoropolymer coatedrelease liner. The coated release liner was dried at 110° F. (43° C.)for 4 minutes, at 185° F. (85° C.) for 2 minutes and then at 225° F.(107° C.) for 2 minutes. The dried material was allowed to cool toambient temperature, then it was laminated to the corona treated surfaceof a 3 mil (76 μm) low density polyethylene film (COTRAN™ 9720).

The release liner was removed from the upper portion then it waslaminated onto the low density polyethylene film surface of the lowerportion. As initially prepared, the resulting composite consisted offive layers: a backing, a first adhesive layer containing 25.8 percentby weight of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, a lowdensity polyethylene membrane, a second adhesive layer that did notcontain drug, and a release liner. Patches were die cut from thecomposite. The patches were allowed to equilibrate for 48 hours prior tothe commencement of skin penetration testing. Skin penetration (humancadaver skin) data is shown in Table 16 below. Each value is the averageof three independent determinations.

                  TABLE 16                                                        ______________________________________                                        Cumulative Amount Penetrating (μm/cm.sup.2)                                2 hr      4 hr   8 hr         12 hr                                                                              24 hr                                      ______________________________________                                        613       897    1269         1549 2260                                       ______________________________________                                    

EXAMPLE 39

An upper portion of a transdermal delivery device identical with that ofExample 38 was prepared.

The lower portion was prepared by knife coating the formulation preparedin Example 38 for the upper portion at a thickness of 17 mils (432 μm)onto a SCOTCHPAK™ 1022 fluoropolymer coated release liner. The coatedrelease liner was allowed to dry at ambient temperature for 20 minutesbefore being laminated to the matte side of a 9% EVA membrane (COTRAN™9702 membrane).

The release liner was removed from the upper portion and it waslaminated to the membrane side of the lower portion. The resultingcomposite consisted of five layers: a backing; a first adhesive layercontaining 25.8 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; a 9% EVA membrane; asecond adhesive layer containing 25.8 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; and a release liner.The composite was die cut into patches. The patches were allowed toequilibrate for 48 hours prior to the commencement of skin penetrationtesting. Skin penetration (human cadaver skin) data is shown in Table 17below. Each value is the average of three separate determinations.

                  TABLE 17                                                        ______________________________________                                        Cumulative Amount Penetrating (μm/cm.sup.2)                                2 hr      4 hr   8 hr         12 hr                                                                              24 hr                                      ______________________________________                                        1420      2330   3431         4185 5571                                       ______________________________________                                    

EXAMPLES 40-45

Dry adhesive (28.6274 g isooctyl acrylate:acrylamide:vinyl acetate75:5:20 copolymer), (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole(9.9572 g), ethyl acetate (64.78 g) and methanol (7.20 g) were placed ina glass jar. The jar was capped then agitated on a platform shaker untila uniform formulation was obtained.

The upper portion of the transdermal delivery device was prepared byknife coating the formulation at a thickness of 30 mils (762 μm) on aSCOTCHPAK™ 1022 fluoropolymer coated release liner. The coated releaseliner was allowed to dry for 60 minutes at ambient temperature then itwas laminated to the polyester side of SCOTCHPAK™ 1109 polyester filmlaminate.

The lower portion was prepared by knife coating the formulation at athickness of 17 mil (432 μm) onto a SCOTCHPAK™ 1022 fluoropolymer coatedrelease liner. The coated release liner was allowed to dry at ambienttemperature for 20 minutes then it was laminated to one of the membranesshown in Table 18 below.

The release liner was removed from the upper portion and then it waslaminated to the membrane surface of the lower portion. The resultingcomposite contained a backing, a first adhesive layer, a membrane, asecond adhesive layer and a release liner. Both adhesive layerscontained 25.8 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole based on the totalweight of drug and adhesive copolymer. The composite was die cut intopatches. Skin penetration (human cadaver skin) data is shown in Table 19below. Each value is the average of three separate determinations.

                  TABLE 18                                                        ______________________________________                                        Example                                                                       Number      Membrane                                                          ______________________________________                                        40          Nylon scrim.sup.1                                                 41          Polyurethane film.sup.2 (2 mil/51 μm)                          42          Macroporous polyethylene.sup.3                                    43          Microporous polyethylene.sup.4 (2 mil/51 μm)                   44          19% EVA.sup.5 (2 mil/51 μm)                                    45          19% EVA.sup.5 (4 mil/102 μm)                                   ______________________________________                                         .sup.1 CEREX ™ HC1616012 (Fiber Web North America, Inc., Simpsonville,     SC)                                                                           .sup.2 Prepared from Dow Medical Grade 236380AE Resin                         .sup.3 DELNET ™ CSD070725 high density polyethylene thermal formed         netting (Applied Extrusion Technologies Inc., Middletown, DE)                 .sup.4 COTRAN ™ 9710                                                       .sup.5 Prepared from ULTRATHENE ™ UE631000 from Quantum Chemical      

                  TABLE 19                                                        ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr      4 hr    8 hr    12 hr 24 hr                                  ______________________________________                                        40     897       1705    2916    3640  4776                                   41     1022      2219    3710    4680  6140                                   42     1114      2246    3738    4649  5981                                   43     1197      2619    4372    5274  6485                                   44     919       1918    3239    4092  5525                                   45     1315      2383    3578    4417  5897                                   ______________________________________                                    

EXAMPLES 46-51

Dry adhesive (25.6671 g of isooctyl acrylate:acrylamide:vinyl acetate75:5:20 copolymer), (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole(6.9005 g), ethyl acetate (54.79 g) and methanol (6.09 g) were placed ina glass jar. The jar was capped then agitated on a platform shaker untila uniform formulation was obtained.

The upper portion of a transdermal delivery device was prepared by knifecoating the formulation at a thickness of 28 mils (711 μm) on aSCOTCHPAK™ 1022 fluoropolymer coated release liner. The coated releaseliner was allowed to dry for 60 minutes at ambient temperature then itwas laminated to the polyester side of SCOTCHPAK™ 1109 polyester filmlaminate.

The lower portion was prepared by knife coating the formulation at athickness of 8 mil (203 μm) onto a SCOTCHPAK™ 1022 fluoropolymer coatedrelease liner. The coated release liner was allowed to dry at ambienttemperature for 20 minutes then it was laminated to one of the membranesshown in Table 20 below.

The release liner was removed from the upper portion and it waslaminated to the membrane surface of the lower portion. The resultingcomposite contained a backing, a first adhesive layer, a membrane, asecond adhesive layer and a release liner. Both adhesive layerscontained 21.1 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole based on the totalweight of drug and adhesive copolymer. The composite was die cut intopatches. Skin penetration (human cadaver skin) data is shown in Table 21below. Each value is the average of three independent determinations.

                  TABLE 20                                                        ______________________________________                                        Example                                                                       Number Membrane                                                               ______________________________________                                        46     Polyurethane film.sup.1 (2 mil/51 μm)                               47     4.5% EVA film.sup.2 (3 mil/76 μm)                                   48     4.5% EVA film.sup.2 (2 mil/51 μm)                                   49     Linear low density polyethylene film.sup.3 (3 mil/76 μm)            50     High density polyethylene film.sup.4 (3 mil/76 μm)                  51     Low density polyethylene film.sup.5 (3 mil/76 μm)                   ______________________________________                                         .sup.1 Prepared from Dow Medical Grade 236380AE Resin                         .sup.2 Prepared from NATR 198 Resin, Quantum Chemical                         .sup.3 Prepared from DOWLEX ™ 2035, Dow Chemical Company                   .sup.4 Prepared from 9720 resin, Dow Chemical Company                         .sup.5 COTRAN ™ 9720, 3M Company                                      

                  TABLE 21                                                        ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr      4 hr    8 hr    12 hr 24 hr                                  ______________________________________                                        46     537       1151    2108    2734  3539                                   47     668       1087    1472    1749  2404                                   48     616       1037    1475    1802  2502                                   49     580       976     1322    1544  2028                                   50     623       915     1068    1117  1210                                   51     623       992     1244    1568  2093                                   ______________________________________                                    

EXAMPLE 53

Dry adhesive (11.9008 g of isooctyl acrylate:acrylamide:vinyl acetate75:5:20 copolymer), (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole(3.0672 g), ethyl acetate (25.04 g) and methanol (2.87 g) were combinedand agitated to provide a uniform formulation. The formulation was knifecoated at a thickness of 21 mil (533 μm) onto a release liner. Thecoated release liner was allowed to dry at ambient temperature for 1hour.

The upper (skin distal) portion of a transdermal delivery device wasprepared by laminating a portion of the dried coated release liner tothe polyester side of SCOTCHPAK™ 1109 polyester film laminate. Therelease liner was removed and the backing/adhesive laminate waslaminated to another portion of the dried coated release liner.

The lower portion of a transdermal delivery device was prepared bylaminating a portion of the dried coated release liner to a 2 mil (51μm) 9% EVA membrane (COTRAN™ 9703).

The release liner was removed from the upper portion and it waslaminated to the membrane surface of the lower portion. In the resultingcomposite, the first adhesive layer was twice as thick as the secondadhesive layer and both contained 20.5 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole. The composite was diecut into patches. The skin penetration (human cadaver skin) data isshown in Table 22 below. Each value is the average of two independentdeterminations.

                  TABLE 22                                                        ______________________________________                                        Cumulative Amount Penetrating (μm/cm.sup.2)                                2 hr      4 hr   8 hr         12 hr                                                                              24 hr                                      ______________________________________                                        440       945    1722         2312 3628                                       ______________________________________                                    

EXAMPLE 53

Transdermal delivery devices were prepared according to the method ofExample 52 except that a 3 mil (76 μm) 19% EVA membrane (prepared fromULTRATHENE™ UE631-000, Quantum Chemical) was used. Skin penetration(human cadaver skin) data is shown in Table 23 below. Each value is theaverage of three independent determinations.

                  TABLE 23                                                        ______________________________________                                        Cumulative Amount Penetrating (μm/cm.sup.2)                                2 hr      4 hr   8 hr         12 hr                                                                              24 hr                                      ______________________________________                                        548       1160   2117         2920 4463                                       ______________________________________                                    

EXAMPLES 54-76

A set of transdermal delivery devices was prepared in which the weightpercent of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole in theadhesive layer, the thickness of the first and second adhesive layersand the membrane composition were varied.

A coating formulation (Formulation A) was prepared by placing dryadhesive (2.7446 g of isooctyl acrylate:acrylamide:vinyl acetate 75:5:20copolymer), drug (0.2548 g of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole), ethyl acetate (5.017g) and methanol (0.557 g) in order into a glass jar. The jar was capped,wrapped in aluminum foil and then agitated on a platform shaker toobtain a uniform formulation. When this formulation was coated onto arelease liner and dried, the resulting adhesive layer contained 8.5percent by weight of drug based on the total weight of drug andadhesive.

Using the same method, four additional coating formulations wereprepared. In each formulation the drug was(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole, the adhesive wasisooctyl acrylate:acrylamide:vinyl acetate 75:5:20 copolymer, thesolvent was 90:10 ethyl acetate:methanol and the percent solids in theformulation was 35 percent. The formulation designation and the weightpercent of drug in the adhesive layer after coating and drying theformulation are as follows: Formulation B-13.0 percent; FormulationC-17.5 percent; Formulation D-22.0 percent; and Formulation E-26.5percent.

The upper portion of the transdermal delivery device was prepared byknife coating the formulation at the designated thickness onto aSCOTCHPAK™ 1022 fluoropolymer coated release liner. The coated releaseliner was allowed to dry at ambient temperature for 20 [4 mil (102 μm)and 8 mil (203 μm) coatings] or 30 minutes [12-20 mil (305-508 μm)coatings] then it was laminated to the polyester side of SCOTCHPAK™ 1109polyester film laminate.

The lower portion of the transdermal delivery device was prepared byknife coating the formulation at the designated thickness onto aSCOTCHPAK™ 1022 fluoropolymer coated release liner. The coated releaseliner was allowed to dry at ambient temperature for 60 minutes then itwas laminated to the designated membrane.

Composites were assembled by removing the release liner from theappropriate upper portion and laminating it to the membrane surface ofthe appropriate lower portion. The resulting composites contained abacking, a first adhesive layer, a membrane, a second adhesive layer anda release liner. The weight percent of drug was the same in both layersof adhesive. The coating formulation used, the coating thickness for theupper and lower portions, and the membrane used to prepare eachcomposite are shown in Table 24 below. Skin penetration (human cadaverskin) data is shown in Table 25 below. Unless otherwise indicated, eachvalue is the average of three independent determinations.

                  TABLE 24                                                        ______________________________________                                                            Coating Thickness                                         Example             (μm)                                                   Number Formulation  Lower   Upper   Membrane                                  ______________________________________                                        54     A            305     737     9% EVA.sup.1                              55     B            203     660     LDPE.sup.2                                56     B            203     660     19% EVA.sup.3                             57     B            203     813     LDPE                                      58     B            203     813     19% EVA                                   59     B            406     660     LDPE                                      60     B            406     660     19% EVA                                   61     B            406     813     LDPE                                      62     B            406     813     19% EVA                                   63     C            102     737     9% EVA                                    64     C            305     584     9% EVA                                    65     C            305     737     9% EVA                                    66     C            305     889     9% EVA                                    67     C            508     737     9% EVA                                    68     D            203     660     LDPE                                      69     D            203     660     19% EVA                                   70     D            203     813     LDPE                                      71     D            203     813     19% EVA                                   72     D            406     660     LDPE                                      73     D            406     660     19% EVA                                   74     D            406     813     LDPE                                      75     D            406     813     19% EVA                                   76     E            305     737     9% EVA                                    ______________________________________                                         .sup.1 COTRAN ™ 9702                                                       .sup.2 Liner low density polyethylene film COTRAN ™ 9720                   .sup.3 Prepared from ULTRATHENE ™ UE631000, Quantum Chemical          

                  TABLE 25                                                        ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr      4 hr    8 hr     12 hr 24 hr                                 ______________________________________                                        54     .sup. 266.sup.1                                                                         .sup.  474.sup.1                                                                      .sup.  661.sup.1                                                                       .sup. .sup.  980.sup.1                      55     336        524     705      836  1138                                  56     241        479     829     1085  1553                                  57     340        534     718      838  1178                                  58     422        757    1219     1575  2281                                  59     408        792    1156     1354  1736                                  60     520        924    1437     1818  2455                                  61     406        792    1171     1369  1739                                  62     460        892    1451     1836  2623                                  63     .sup. 391.sup.1                                                                         .sup.  559.sup.1                                                                      .sup.  763.sup.1                                                                       .sup. .sup. 1421.sup.1                      64     .sup. 609.sup.1                                                                         .sup. 1056.sup.1                                                                      .sup. 1415.sup.1                                                                       .sup. 1648.sup.1                                                                    .sup. 2064.sup.1                      65     .sup. 731.sup.3                                                                         .sup. 1244.sup.3                                                                      .sup. 1708.sup.3                                                                       .sup. 1981.sup.3                                                                    .sup. 2377.sup.3                      66     .sup. 698.sup.1                                                                         .sup. 1200.sup.1                                                                      .sup. 1589.sup.1                                                                       .sup. 1817.sup.1                                                                    .sup. 2326.sup.1                      67     .sup. 792.sup.1                                                                         .sup. 1495.sup.1                                                                      .sup. 2098.sup.1                                                                       .sup. 2423.sup.1                                                                    .sup. 2936.sup.1                      68     658       1014    1340     1566  2161                                  69     969       1549    2314     2776  3402                                  70     794       1169    1504     1768  2399                                  71     715       1289    2095     2758  3834                                  72     989       1697    2326     2681  3318                                  73     938       1704    2625     3218  4284                                  74     824       1547    2231     2569  3238                                  75     959       1749    2755     3509  4604                                  76     .sup. 1256.sup.2                                                                        .sup. 1943.sup.2                                                                      .sup. 2533.sup.2                                                                       .sup. 2854.sup.2                                                                    .sup. 3641.sup.2                      ______________________________________                                         .sup.1 Average of 6 independent determinations                                .sup.2 Average of 5 independent determinations                                .sup.3 Average of 18 independent determinations                          

EXAMPLE 77

Dry adhesive (818.1 g of isooctyl acrylate:acrylamide:vinyl acetate74:6:20 copolymer), (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole(284.4 g), ethyl acetate (1842.8 g) and methanol (204.7 g) were placedin a glass jar. The jar was capped then agitated on a platform shakeruntil a uniform formulation was obtained.

The upper portion of the transdermal delivery device was prepared byknife coating the formulation at a thickness of 32 mils (813 μm) onto aSCOTCHPAK™ 1022 fluoropolymer coated release liner. The coated releaseliner was allowed to dry for 60 minutes at ambient temperature then itwas laminated to the polyester side of SCOTCHPAK™ 1109 polyester filmlaminate.

The lower portion was prepared by knife coating the formulation at athickness of 16 mil (406 μm) onto a SCOTCHPAK™ 1022 fluoropolymer coatedrelease liner. The coated release liner was allowed to dry at ambienttemperature for 60 minutes then it was laminated to the matte side of aCOTRAN™ 9702 membrane.

The release liner was removed from the upper portion and then it waslaminated to the membrane surface of the lower portion. The resultingcomposite contained a backing, a first adhesive layer, a membrane, asecond adhesive layer and a release liner. Both adhesive layerscontained 25.8 percent by weight of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole based on the totalweight of drug and adhesive copolymer. The composite was die cut intopatches. Skin penetration (human cadaver skin)data is shown in Table 26below. Each value is the average of three independent determinations.

                  TABLE 26                                                        ______________________________________                                        Cumulative Amount Penetrating (μm/cm.sup.2)                                2 hr      4 hr   8 hr         12 hr                                                                              24 hr                                      ______________________________________                                        551       1110   1912         2548 3833                                       ______________________________________                                    

EXAMPLES 78-82

The penetration of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazolefrom excipient solutions through human cadaver skin was assessed asfollows. Solutions containing 30 mg of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole per mL of excipientwere prepared by combining 240 mg of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole with 8 mL of one ofthe excipients listed in Table 27 below and agitating the mixture on aplatform shaker until a solution was obtained. Skin penetration wasmeasured using the test method described above with the followingchanges: a patch was not placed on the skin prior to cell assembly andafter the cell was assembled a 2 mL portion of the solution containingdrug in excipient was added to the upper portion of the cell. The skinpenetration (human cadaver skin) data is shown in Table 28 below. Eachvalue is the average of two independent determinations.

                  TABLE 27                                                        ______________________________________                                        Example                                                                       Number      Excipient                                                         ______________________________________                                        78          Lauryl alcohol                                                    79          Ethyl oleate                                                      80          Oleic acid                                                        81          Oleyl alcohol                                                     82          Poly(ethylene glycol-400) monolaurate                             Control     0.1M Phosphate buffer (pH 6)                                      ______________________________________                                    

                  TABLE 28                                                        ______________________________________                                        Example                                                                              Cumulative Amount Penetrating (μm/cm.sup.2)                         Number 2 hr    4 hr     8 hr  12 hr  24 hr 48 hr                              ______________________________________                                        78     0       23       130   287    1146  3342                               79     19      87       286   524    1371  2967                               80     0       0        14    32     122   356                                81     0       18       90    191    627   1613                               82     0       1        17    41     146   409                                Control                                                                              2       22       80    164    482   868                                ______________________________________                                    

What is claimed is:
 1. A transdermal delivery device comprising:(A) abacking; (B) an adhesive layer adhered to one surface of the backing andcomprising a homogeneous mixture of(1) a copolymer comprising(a) about80 to 98 percent by weight of an alkyl acrylate or methacrylatecontaining 4 to 10 carbon atoms in the alkyl group, based on the weightof all monomers in the copolymer; and (b) about 2 to 20 percent byweight of a monomer selected from the group consisting of acrylic acid,methacrylic acid, an alkyl acrylate or methacrylate containing 1 to 3carbon atoms in the alkyl group, acrylamide, methacrylamide, a loweralkyl substituted acrylamide, diacetone acrylamide andN-vinyl-2-pyrrolidone, based on the weight of all monomers in thecopolymer; and (2) a therapeutically effective amount of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole.
 2. A transdermaldelivery device according to claim 1, wherein the(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is present in anamount of about 5 to about 35 percent by weight based on the totalweight of the adhesive layer.
 3. A transdermal delivery device accordingto claim 1 wherein the (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazoleis present in an amount of about 10 to about 30 percent by weight basedon the total weight of the adhesive layer.
 4. A transdermal deliverydevice according to claim 1, wherein the copolymer comprises isooctylacrylate.
 5. A transdermal delivery device according to claim 1, whereinthe copolymer comprises acrylic acid.
 6. A transdermal delivery deviceaccording to claim 1, wherein the adhesive layer further comprises askin penetration enhancer.
 7. A transdermal delivery devicecomprising:(A) a backing; (B) an adhesive layer adhered to one surfaceof the backing and comprising a homogeneous mixture of(1) a copolymercomprising(a) about 60 to 80 percent by weight of an alkyl acrylate ormethacrylate containing 4 to 10 carbon atoms in the alkyl group, basedon the weight of all monomers in the copolymer; (b) about 4 to 9 percentby weight of a monomer selected from the group consisting of acrylicacid, methacrylic acid, an alkyl acrylate or methacrylate containing 1to 3 carbon atoms in the alkyl group, acrylamide, methacrylamide, alower alkyl substituted acrylamide, diacetone acrylamide andN-vinyl-2-pyrrolidone, based on the weight of all monomers in thecopolymer; and (c) about 15 to 35 percent by weight of vinyl acetate,based on the weight of all monomers in the copolymer; and (2) atherapeutically effective amount of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole.
 8. A transdermaldelivery device according to claim 7, wherein the(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is present in anamount of about 5 to about 35 percent by weight based on the totalweight of the adhesive layer.
 9. A transdermal delivery device accordingto claim 7, wherein the(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is present in anamount of about 10 to about 30 percent by weight based on the totalweight of the adhesive layer.
 10. A transdermal delivery deviceaccording to claim 7, wherein the copolymer comprises the acrylate ormethacrylate in an amount of about 70 to 80 percent by weight based onthe total weight of all monomers in the copolymer.
 11. A transdermaldelivery device according to claim 7, wherein the copolymer comprisesisooctyl acrylate.
 12. A transdermal delivery device according to claim7, wherein the copolymer comprises acrylamide.
 13. A transdermaldelivery device according to claim 7, wherein the adhesive layer furthercomprises a skin penetration enhancer.
 14. A transdermal delivery devicecomprising:(A) a backing; (B) a first adhesive layer adhered to onesurface of the backing and comprising an adhesive selected from thegroup consisting of:(1) a copolymer comprising(a) about 80 to 98 percentby weight of an alkyl acrylate or methacrylate containing 4 to 10 carbonatoms in the alkyl group, based on the weight of all monomers in thecopolymer; and (b) about 2 to 20 percent by weight of a monomer selectedfrom the group consisting of acrylic acid, methacrylic acid, an alkylacrylate or methacrylate containing 1 to 3 carbon atoms in the alkylgroup, acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and (2) a copolymer comprising(a) about60 to 80 percent by weight of an alkyl acrylate or methacrylatecontaining 4 to 10 carbon atoms in the alkyl group, based on the weightof all monomers in the copolymer; (b) about 4 to 9 percent by weight ofa monomer selected from the group consisting of acrylic acid,methacrylic acid, an alkyl acrylate or methacrylate containing 1 to 3carbon atoms in the alkyl group, acrylamide, methacrylamide, a loweralkyl substituted acrylamide, diacetone acrylamide andN-vinyl-2-pyrrolidone, based on the weight of all monomers in thecopolymer; and (c) about 15 to 35 percent by weight of vinyl acetate,based on the weight of all monomers in the copolymer; (C) a secondadhesive layer comprising an adhesive selected from the group consistingof:(1) a copolymer comprising(a) about 80 to 98 percent by weight of analkyl acrylate or methacrylate containing 4 to 10 carbon atoms in thealkyl group, based on the weight of all monomers in the copolymer; and(b) about 2 to 20 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer; and (2) a copolymer comprising(a) about60 to 80 percent by weight of an alkyl acrylate or methacrylatecontaining 4 to 10 carbon atoms in the alkyl group, based on the weightof all monomers in the copolymer; (b) about 4 to 9 percent by weight ofa monomer selected from the group consisting of acrylic acid,methacrylic acid, an alkyl acrylate or methacrylate containing 1 to 3carbon atoms in the alkyl group, acrylamide, methacrylamide, a loweralkyl substituted acrylamide, diacetone acrylamide andN-vinyl-2-pyrrolidone, based on the weight of all monomers in thecopolymer; and (c) about 15 to 35 percent by weight of vinyl acetate,based on the weight of all monomers in the copolymer; and (D) a membranebetween the first and second adhesive layers, the membrane beingpermeable to (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole,whereinat least one of said first and second adhesive layers further comprisesa therapeutically effective amount of(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole in admixturetherewith.
 15. A transdermal delivery device according to claim 14,wherein the (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is presentin both the first and second adhesive layers in an amount of about 5 to35 percent by weight based on the total weight of each such adhesivelayer.
 16. A transdermal delivery device according to claim 14, whereinthe (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole is present in boththe first and second adhesive layers in an amount of about 10 to 30percent by weight based on the total weight of each such first andsecond adhesive layer.
 17. A transdermal delivery device according toclaim 14, wherein the both the first and second adhesive layer comprisea copolymer comprising:(a) about 80 to 98 percent by weight of an alkylacrylate or methacrylate containing 4 to 10 carbon atoms in the alkylgroup, based on the weight of all monomers in the copolymer; and (b)about 2 to 20 percent by weight of a monomer selected from the groupconsisting of acrylic acid, methacrylic acid, an alkyl acrylate ormethacrylate containing 1 to 3 carbon atoms in the alkyl group,acrylamide, methacrylamide, a lower alkyl substituted acrylamide,diacetone acrylamide and N-vinyl-2-pyrrolidone, based on the weight ofall monomers in the copolymer.
 18. A transdermal delivery deviceaccording to claim 17 wherein the copolymer in the first and secondadhesive layers comprises isooctyl acrylate.
 19. A transdermal deliverydevice according to claim 17, wherein the copolymer in the first andsecond adhesive layers comprises acrylic acid.
 20. A transdermaldelivery device according to claim 14, wherein both the first and secondadhesive layers further comprise a skin penetration enhancer.